Preparation of α-amino phosphonic acid derivatives

ABSTRACT

This invention relates to a process for preparing α-amino phosphonic acid derivatives which comprises reacting a nitrile with a phosphite ester under hydrogenation conditions; and to the α-amino phosphonic acid derivatives formed and uses thereof.

Previous methods for the preparation of α-amino phosphonic acidderivatives required complicated reactions involving many steps and theuse of sophisticated reagents.

We now have discovered a process for the preparation of α-aminophosphonic acid derivatives by a process which comprises reactingnitriles under hydrogenation conditions.

The key step in our process is the generation of an imine, R--CH=NH, inpresence of a phosphite ##STR1##so that the phosphite adds to the imineto form a C-P bond. The imine is generated by hydrogenation of anitrile. Thus the process is simply hydrogenation of a nitrile inpresence of a phosphite.

The equation 1 summarizes the process: ##STR2##

The product A can react further via its primary amino group adding tofurther imine formed in the reduction process. This step is shown inequation 2. ##STR3##

An additional possibility is that the imine is further reduced withoutbeing intercepted by phosphite or by α-amino phosphonate yielding thesimple amine R₁ CH₂ NH₂ as shown in equation 3. ##STR4##

In practice products A, B and C are all found. The whole process issummarized below: ##STR5## In principle any catalyst which is capable ofbringing about reduction of a nitrile can be used in this process. Suchcatalysts include platinum, palladium, rhodium on various supports,Raney nickel, etc. The phosphites exert a modifying effect to thecatalytic activity of the catalysts to varying degrees. In general thereduction process is significantly slower in presence of the phosphite.The preferred catalyst for this process is Raney nickel.

The reduction process can be carried out on mixtures of nitrile andphosphite in various ratios with or without solvent. Suitable solventsinclude hydrocarbons such as hexane, cyclohexane, benzene, toluene,etc.; alcohols such as methanol, ethanol, butanol, isopropanol, etc.;ethers such as tetrahydrofuran. The ratio of nitrile to phosphite canvary from 1:1 to 1:10 or higher. With higher amounts of phosphite yieldsof product A increase and amounts of C significantly decrease.

The reaction conditions can vary widely depending on the particularsystem actually employed. For example, the reduction process can becarried out at temperatures from 20° C. to 150° C. and hydrogenpressures from 40 to 2000 psi. The preferred conditions are 30°-100° C.and pressures from 100 to 1000 psi of hydrogen.

The process is applicable to a wide range of nitriles for examplealiphatic nitriles such as acetonitrile, propionitrile, butyronitrile,lauric acid nitrile, stearonitrile; aryl nitriles such as toluonitriles,chlorobenzonitrile; or heterocyclic nitriles such as nicotinic acidnitrile, isonicotinic acid nitrile, etc. Compounds bearing more than onenitrile group can be employed such as aliphatic dinitriles such asmalononitrile, glutaronitrile, adiponitrile, etc,; aryl dinitriles suchas phthalonitrile, etc. Polymers or copolymer nitriles can also beutilized such as polyacrylonitrile, polymethacrylonitrile, or copolymersof acrylonitrile or methacrylonitrile with vinyl monomers such asethylene, styrene, vinyltoluene, etc.

The phosphite component includes virtually all phosphites of the generalformula ##STR6##where R² and R³ are alkyl, aryl, aralkyl or where R² andR³ form a ring. Examples include dimethyl phosphite, diethyl phosphite,dipropylphosphite, diisopropyl phosphite, dibutyl phosphite, dilaurylphosphite, dioctylphosphite, diphenylphosphite, di-p-tolyl phosphite,etc.

Cyclic phosphites include: ##STR7##

The phosphonate esters A and B can be readily hydrolysed, for example,with acid or base to yield the corresponding phosphonic acids. ##STR8##In cases where R¹ is aryl the product E is readily converted into D byhydrogenolysis. ##STR9## The relative simplicity of the present processis unexpected since previous routes to products A and D have requirednumerous steps and sophisticated reagents.

The following examples are presented by way of illustration and not oflimitation.

EXAMPLE 1

To a solution of benzonitrile (75g; 0.73 mole) in diethyl phosphite(200g; 1.45 mole) was added W-2 Raney nickel (6g) and the whole mixturecharged in an autoclave. The reactor was pressured to 600 psi withhydrogen and the mixture heated to 60° C. The pressure was maintained at550-600 psi by addition of hydrogen as the reduction proceeded. After 18hours, uptake of hydrogen had ceased. After cooling hydrogen wasreleased and the catalyst filtered as the reaction product was removedfrom the reactor. Excess diethyl phosphite and unreacted benzonitrilewas removed (135g) by distillation under reduced pressure. The residuewas diethyl N-benzyl α-aminobenzylphosphonate. Hydrolysis of thisresidue with 18% HCl after crystallization yielded N-benzyl α-aminobenzylphosphonic acid, 83g (82%), mp 233°-6°. ##STR10##

Analysis. Found N, 4.91; P, 11.05.

Calculated for C₁₄ H₁₆ NO₃ P:N, 5.05; P, 11.18.

Nmr spectrum was in accord with the assigned structure.

EXAMPLE 2

This example illustrates formation of diethyl α-amino benzylphosphonateas the major reaction product. ##STR11##

Into an autoclave were charged benzonitrile (90g; .88 mole), diethylphosphite (250g; 1.8 mole) and W-2 Raney nickel (5g). The mixture washeated at 87°-90° under a hydrogen pressure of 170-200 psi for 18 hours.The catalyst was filtered and the product freed from excess diethylphosphate and unreacted benzonitrile by heating at 70° under reducedpressure. A small amount of solid formed which was filtered anddiscarded. Pure diethyl α-amino benzylphosphonate was obtained from theresulting liquid as follows. Dry hydrochloric acid gas was passed intocrude product for 2 hours followed by addition of ether. The resultingsolid was filtered and after crystallization from ethanol/ether gavepure diethyl α-amino benzylphosphonate hydrochloride mp 135°-140°, 37g.Nmr spectrum indicated pure sample.

Analysis: Found: N, 4.85; P, 10.80; Cl, 13.06; eq. wt. 283 Calculatedfor C₁₁ H₁₉ NO₃ PCl: N, 5.01; P, 11.09; Cl, 12.70, eq. wt. 279.5.

EXAMPLE 3

This example illustrates the use of a solvent. To a solution ofm-toluonitrile (58.5g; 0.5 mole) and diethyl phosphite (70g; 0.51 mole)in cyclohexane (200 ml) in an autoclave was added Raney nickel (10g).The solution was heated to 60° and pressured to 600 psi with hydrogen.Heating was continued at 55°-60° with hydrogen pressure maintained at500 -600 psi by re-pressuring as necessary. After 24 hours hydrogenuptake had ceased. Solvent and unreacted starting materials were removedby distillation under reduced pressure to yield 110g of crude ester.##STR12## Hydrolysis of this crude ester with 18% hydrochloric acidyielded the corresponding acid, mp. 233°-5°.

Analysis, calculated for C₁₆ H₂₀ NO₃ P; N, 4.59; P, 10.16. Found: N,4.65; P, 9.70.

EXAMPLE 4

In autoclave was charged o-chlorobenzonitrile (50g; 0.365 mole), diethylphosphite (220g; 1.6 mole) and Raney nickel (10g). The mixture wasreduced under a hydrogen pressure of 530-600 psi at 57°-62° for 20 hr.at which time hydrogen uptake had ceased. Unreacted phosphite andnitrile were removed from the reaction mixture after filtration of thecatalyst. The resulting crude ester was hydrolysed with 18% hydrochloricacid to yield a white solid. Recrystallization from aqueous acetic acidyield pure N(2-chlorobenzyl)-α-amino 2-chlorobenzylphosphonic acid mp205°-7°. ##STR13##

Analysis: calculated for C₁₁ H₁₄ Cl₂ NO₃ P: N, 4.05; P, 8.96. Found: N,3.95; P, 8.63.

EXAMPLE 5 The use of an aliphatic nitrile.

A solution of propionitrile (27.5g; 0.5 mole) and diethyl phosphite(70g; 0.51 mole) in cyclohexane (200 ml) was reduced in presence ofRaney nickel (10g) at 55°-60° and hydrogen pressure of 560-600 psi.Uptake of hydrogen ceased after 6 hours. Unreacted starting materialsand solvent were removed by distillation to yield 20g of crude ester.This was further purified by dissolving in ether and saturating thesolution with HCl whereupon the hydrochloride of diethyl N-propylα-aminopropylphosphonate separated. ##STR14##

This product was characterized by its nmr spectrum. Hydrolysis of thisester yielded N-propyl α-aminopropylphosphonic acid as a hydroscopicoil. The nmr spectrum was consistent with the assigned structure.

EXAMPLE 6

A solution of benzonitrile (52g; 0.5 mole) and dibutyl phosphite (38.8g;0.2 mole) in cyclohexane (200 ml) was hydrogenated at 500 -600 psi ofhydrogen at 55°-57° in presence of Raney nickel (10g) for 24 hrs.Removal of solvent yielded an oil which contained a significant amountof unreacted nitrile. Saturation with anhydrous HCl gas led toseparation of an oil 40g (50%) shown by nmr to be dibutyl N-benzylα-aminobenzylphosphonate hydrochloride. Hydrolysis of a portion of thisester gave N-benzyl α-aminobenzylphosphonic acid identical to that ofExample 1.

EXAMPLE 7 This example illustrates the use of an aryl phosphite.

A solution of benzonitrile (52g; 0.5 mole) and diphenyl phosphite (160g;0.7 mole) in cylcohexane (150 ml) was hydrogenated in presence of Raneynickel (8g) at 60°-65° and 500-600 psi of hydrogen. After 18 hrs.hydrogen uptake ceased and after cooling the catalyst was filtered.Evaporation of solvent yielded crude product containing unreactedbenzonitrile and diphenyl phosphite. Chromatography on alumina frombenzene yielded by elution with chloroform/benzene diphenyl N-benzylα-aminobenzylphosphonate as an oil. IR and Nmr were consistent with theassigned structure. ##STR15##

The compositions of this invention have a wide variety of uses. They areparticularly useful as

Scale inhibitors,

Corrosion inhibitors -- particularly for oxygen containing systems, andas

Chelating agents.

We claim:
 1. A process of preparing an α-aminophosphonic acid derivativewhich comprises reacting a nitrile with a phosphite ester of the generalformula ##STR16##where R² and R³ are alkyl, aryl, aralkyl or where R²and R³ together form a ring structure in a ratio of nitrile to phosphiteof about 1:1 to about 1:10 or more at a temperature from about 20° C. toabout 150° C. and hydrogen pressures of about 40 to about 200 psi underhydrogenation conditions.
 2. The process of claim 1 where theα-aminophosphonic acid derivatives formed comprise those of the formula##STR17## ##STR18##where R¹ is a hydrocarbon group and R² is ahydrocarbon group.
 3. The process of claim 2 where R¹ is an arylicgroup.
 4. The process of claim 3 where the arylic group is a phenyl or asubstituted phenyl group.
 5. The process of claim 4 where ##STR19##whereX is hydrogen, alkyl, halogen or combinations thereof.
 6. The process ofclaim 2 where R¹ is aliphatic.
 7. The process of claim 1 where anadditional step of hydrolization is carried out to produce anα-aminophosphonic acid.
 8. The process of claim 7 where the hydrolysisis carried out using hydrochloric acid.
 9. The process of claim 7 wherethe α-aminophosphonic acids formed comprise those of the formula##STR20##10.
 10. The process of claim 1 where the nitrile m-toluonitrileand the phosphite ester is diethyl phosphite.
 11. The process of claim 7where the nitrile is m-toluonitrile, the phosphite ester is diethylphosphite and the final product obtained is